Gray Thomas, Coakley Ray, Hirsh Andrew, Thornton David, Kirkham S, Koo Ja-Seok, Burch Lauranell, Boucher Richard, Nettesheim Paul
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Feb;286(2):L320-30. doi: 10.1152/ajplung.00440.2002. Epub 2003 Oct 3.
Mucociliary transport in the airways significantly depends on the liquid and mucin components of the airway surface liquid (ASL). The regulation of ASL water and mucin content during pathological conditions is not well understood. We hypothesized that airway epithelial mucin production and liquid transport are regulated in response to inflammatory stimuli and tested this hypothesis by investigating the effects of the pleiotropic, early-response cytokine, IL-1beta, on cultured primary human bronchial epithelial and second-passage, normal human tracheo-bronchial epithelial (NHTBE) cell cultures. Fully differentiated NHTBE cultures secreted two major airway mucins, MUC5AC and MUC5B. IL-1beta, in a dose- and time-dependent manner, increased the secretion of MUC5AC, but not MUC5B. MUC5AC mRNA levels were only transiently increased at 1 and 4 h after the start of IL-1beta treatment and returned to control levels thereafter, even though MUC5AC mucin production remained elevated for at least 72 h. Synchronous with elevated MUC5AC secretion, ASL volume increased, its percentage of solid was reduced, and the pH/[HCO(3)(-)] of the ASL was elevated. ASL volume changes reflected altered ion transport, including an upregulation of Cl(-) secretory currents (via CFTR and Ca(2+)-activated Cl(-) conductance) and an inhibition of epithelial sodium channel (ENaC)-mediated absorptive Na(+) currents. IL-1beta increased CFTR mRNA levels without affecting those for ENaC subunits. The synchronous regulation of ASL mucin and liquid metabolism triggered by IL-1beta may be an important defense mechanism of the airway epithelium to enhance mucociliary clearance during airway inflammation.
气道中的黏液纤毛运输很大程度上依赖于气道表面液体（ASL）的液体和黏蛋白成分。在病理状态下，ASL水分和黏蛋白含量的调节机制尚不清楚。我们推测气道上皮黏蛋白的产生和液体运输是对炎症刺激作出的反应而受到调节，并通过研究多效性早期反应细胞因子白细胞介素-1β（IL-1β）对原代人支气管上皮细胞培养物以及第二代正常人气管支气管上皮（NHTBE）细胞培养物的影响来验证这一假设。完全分化的NHTBE培养物分泌两种主要的气道黏蛋白，即MUC5AC和MUC5B。IL-1β以剂量和时间依赖性方式增加MUC5AC的分泌，但不增加MUC5B的分泌。在开始IL-1β处理后的1小时和4小时，MUC5AC mRNA水平仅短暂升高，此后恢复到对照水平，尽管MUC5AC黏蛋白的产生至少持续升高72小时。与MUC5AC分泌增加同步，ASL体积增加，其固体成分百分比降低，ASL的pH/[HCO₃⁻]升高。ASL体积变化反映了离子转运的改变，包括Cl⁻分泌电流上调（通过囊性纤维化跨膜传导调节因子和Ca²⁺激活的Cl⁻电导）以及上皮钠通道（ENaC）介导的Na⁺吸收电流受到抑制。IL-1β增加CFTR mRNA水平，但不影响ENaC亚基的mRNA水平。IL-1β触发的ASL黏蛋白和液体代谢的同步调节可能是气道上皮在气道炎症期间增强黏液纤毛清除的重要防御机制。
